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1
Cantarini, L., N. Volpi, P. Carbotti, G. Greco, M. Aglianò, F. Bellisai, F. Giannini, C. Alessandrini, G. Grasso, and M. Galeazzi. "Eosinophilia-associated muscle disorders: an immunohistological study with tissue localisation of major basic protein in distinct clinicopathological forms." Journal of Clinical Pathology 62, no. 5 (January 12, 2009): 442–47. http://dx.doi.org/10.1136/jcp.2008.060616.
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Aims:(a) To evaluate tissue eosinophil density, location of eosinophil cytotoxic products, histopathological muscle changes and inflammatory cell types in different eosinophilia-associated myopathies that are clinicopathologically heterogeneous. (b) To determine the immunohistological range of tissue eosinophil density in non-eosinophilic inflammatory myopathies.Methods:Muscle biopsy specimens from seven patients with blood and/or tissue eosinophilia and clinicolaboratory myopathic signs (five chronic course myopathies, one subacute onset fasciitis/myositis, one acute myositis), and from 18 non-eosinophilic inflammatory myopathies, underwent routine staining, inflammatory infiltrate immunophenotyping, immunostaining for eosinophil major basic protein (MBP) and transmission electron microscopy examination. Eosinophil and total inflammatory cell counts were statistically analysed.Results:Histological examination showed occasional or no infiltrating eosinophils in all cases. MBP staining showed that tissue eosinophil density and percentages in eosinophilia-associated myopathies were significantly higher than in idiopathic myositides. Extracellular MBP diffusion, the hallmark of eosinophil cytotoxicity, was recurrent on sarcolemma and endothelium. Electron microscopy showed eosinophils close to sarcolemma, abundant mast cells, and capillary endothelial swelling. Immunostaining detected a higher mean eosinophil density in idiopathic myositides than previously assessed histologically.Conclusions:MBP immunohistology on skeletal muscle, previously performed only for acute eosinophilic polymyositis, suggests that eosinophil-mediated injury of muscle cells may occur in a wider spectrum of less aggressive eosinophilia-associated myopathies than previously thought. As conventional histology is likely to underestimate this leucocyte subset, MBP staining may be a useful tool in the analysis of tissue infiltration of eosinophils as a possible treatment target.
2
Oliver, Brian, Katrina Tonga, David Darley, Sandra Rutting, Xin Zhang, Hui Chen, and Gang Wang. "COPD treatment choices based on blood eosinophils: are we there yet?" Breathe 15, no. 4 (December 2019): 318–23. http://dx.doi.org/10.1183/20734735.0254-2019.
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Eosinophils are increasingly being recognised as an important characteristic feature of COPD. Patients with COPD and eosinophilic inflammation tend to respond to steroid therapy; however, many questions remain regarding the optimum measurement. Eosinophilic inflammation may be defined based on various sampling techniques, including eosinophil levels in blood, sputum, bronchoalveolar lavage or biopsy, which leads to inconsistencies in its definition. Blood eosinophils may increase in conjunction with sputum eosinophils during COPD exacerbations and therefore may be a good surrogate marker of airway eosinophilic inflammation. However, the timing of the blood eosinophil measurement, the stability of the eosinophil count and the threshold used in different studies are variable. The use of blood eosinophil count to direct biological therapies in COPD has also had variable outcomes. Eosinophilic inflammation has an important role in COPD management; however, its use as the optimum biomarker still needs further investigation.Key pointsEosinophilia may play a significant role in the pathogenesis of COPD.Eosinophilic inflammation in COPD can be steroid responsive; however, eosinophilic inflammation is variable, and caution needs to be taken with measurements and the thresholds used.The long-term effects of reducing eosinophil levels in COPD is unclear.Educational aimsTo explore current knowledge of eosinophils in COPD.To explore the relationship between eosinophilia and corticosteroid use.To understand the limitations of assessing and using eosinophilia in COPD.
3
Desreumaux, P., A. Janin, S. Dubucquoi, MC Copin, G. Torpier, A. Capron, M. Capron, and L. Prin. "Synthesis of interleukin-5 by activated eosinophils in patients with eosinophilic heart diseases." Blood 82, no. 5 (September 1, 1993): 1553–60. http://dx.doi.org/10.1182/blood.v82.5.1553.1553.
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Abstract Eosinophilic endomyocardial disease represents a major evolutive risk in chronic eosinophilia-associated disorders. Eosinophil granule proteins appear to be involved in cardiac injury, but the mechanisms leading to eosinophil infiltration and degranulation are not clear. Interleukin-5 (IL-5) has been recently shown to be produced by eosinophils and might play a role in both chemoattraction and degranulation of eosinophils. In four cases of eosinophilic diseases with severe cardiac failure, we evaluated the proportion of eosinophil phenotypes and the serum levels of eosinophil cationic protein (ECP) and soluble IL-2 receptor (sIL-2R), markers of disease activity in the hypereosinophilic syndromes. All four patients showed a markedly increased proportion of hypodense eosinophils with elevated serum ECP and sIL-2R levels. In all four patients, extracellular deposition of eosinophil granule proteins and features of eosinophil activation were observed in cardiac tissues. The synthesis of IL-5 by eosinophils was detected in myocardial sections and blood cells by in situ hybridization and by immunostaining with a monoclonal antibody against human IL-5. Sixty percent to 90% of tissue eosinophils expressed IL-5 mRNA and IL-5 protein. These data suggest that IL-5 can be produced by eosinophils at the sites of myocardial tissue damage and might participate in local eosinophil activation.
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Desreumaux, P., A. Janin, S. Dubucquoi, MC Copin, G. Torpier, A. Capron, M. Capron, and L. Prin. "Synthesis of interleukin-5 by activated eosinophils in patients with eosinophilic heart diseases." Blood 82, no. 5 (September 1, 1993): 1553–60. http://dx.doi.org/10.1182/blood.v82.5.1553.bloodjournal8251553.
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Eosinophilic endomyocardial disease represents a major evolutive risk in chronic eosinophilia-associated disorders. Eosinophil granule proteins appear to be involved in cardiac injury, but the mechanisms leading to eosinophil infiltration and degranulation are not clear. Interleukin-5 (IL-5) has been recently shown to be produced by eosinophils and might play a role in both chemoattraction and degranulation of eosinophils. In four cases of eosinophilic diseases with severe cardiac failure, we evaluated the proportion of eosinophil phenotypes and the serum levels of eosinophil cationic protein (ECP) and soluble IL-2 receptor (sIL-2R), markers of disease activity in the hypereosinophilic syndromes. All four patients showed a markedly increased proportion of hypodense eosinophils with elevated serum ECP and sIL-2R levels. In all four patients, extracellular deposition of eosinophil granule proteins and features of eosinophil activation were observed in cardiac tissues. The synthesis of IL-5 by eosinophils was detected in myocardial sections and blood cells by in situ hybridization and by immunostaining with a monoclonal antibody against human IL-5. Sixty percent to 90% of tissue eosinophils expressed IL-5 mRNA and IL-5 protein. These data suggest that IL-5 can be produced by eosinophils at the sites of myocardial tissue damage and might participate in local eosinophil activation.
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Bates, Alan W. H. "Diagnosing Eosinophilic Colitis: Histopathological Pattern or Nosological Entity?" Scientifica 2012 (2012): 1–9. http://dx.doi.org/10.6064/2012/682576.
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Reports of “eosinophilic colitis”—raised colonic mucosal eosinophil density in patients with lower gastrointestinal symptoms—have increased markedly over the last fifteen years, though it remains a rarity. There is no consensus over its diagnosis and management, and uncertainty is compounded by the use of the same term to describe an idiopathic increase in colonic eosinophils and an eosinophilic inflammatory reaction to known aetiological agents such as parasites or drugs. In patients with histologically proven colonic eosinophilia, it is important to seek out underlying causes and careful clinicopathological correlation is advised. Because of the variability of eosinophil density in the normal colon, it is recommended that histological reports of colonic eosinophilia include a quantitative morphometric assessment of eosinophil density, preferably across several sites. Few reported cases of “eosinophilic colitis” meet these criteria. As no correlation has been shown between colonic eosinophil density and symptoms in older children or adults, it is suggested that treatment should be directed towards alleviation of symptoms and response to treatment assessed clinically rather than by histological estimates of intramucosal eosinophils.
6
Van Hulst, Glenn, Fabrice Bureau, and Christophe J. Desmet. "Eosinophils as Drivers of Severe Eosinophilic Asthma: Endotypes or Plasticity?" International Journal of Molecular Sciences 22, no. 18 (September 21, 2021): 10150. http://dx.doi.org/10.3390/ijms221810150.
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Asthma is now recognized as a heterogeneous disease, encompassing different phenotypes driven by distinct pathophysiological mechanisms called endotypes. Common phenotypes of asthma, referred to as eosinophilic asthma, are characterized by the presence of eosinophilia. Eosinophils are usually considered invariant, terminally differentiated effector cells and have become a primary therapeutic target in severe eosinophilic asthma (SEA) and other eosinophil-associated diseases (EADs). Biological treatments that target eosinophils reveal an unexpectedly complex role of eosinophils in asthma, including in SEA, suggesting that “not all eosinophils are equal”. In this review, we address our current understanding of the role of eosinophils in asthma with regard to asthma phenotypes and endotypes. We further address the possibility that different SEA phenotypes may involve differences in eosinophil biology. We discuss how these differences could arise through eosinophil “endotyping”, viz. adaptations of eosinophil function imprinted during their development, or through tissue-induced plasticity, viz. local adaptations of eosinophil function through interaction with their lung tissue niches. In doing so, we also discuss opportunities, technical challenges, and open questions that, if addressed, might provide considerable benefits in guiding the choice of the most efficient precision therapies of SEA and, by extension, other EADs.
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Shigemoto, Emi, Masashi Mizuno, Yasuhiro Suzuki, Kazuma Kobayashi, Fumiko Sakata, Tetsuyoshi Kariya, Takayuki Katsuno, Shoichi Maruyama, and Yasuhiko Ito. "Increase of Eosinophil in Dialysate during Induction of Peritoneal Dialysis." Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 39, no. 1 (January 2019): 90–92. http://dx.doi.org/10.3747/pdi.2017.00205.
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As a rare complication in patients on peritoneal dialysis (PD), increase of eosinophil (peritoneal dialysate fluid [PDF] eosinophilia), including eosinophilic peritonitis, was observed in PDF. The majority of eosinophilic peritonitis cases are detected during the early phase of PD induction. However, the frequency of and mechanisms underlying PDF eosinophilia remain unclear. We therefore investigated the frequency of PDF eosinophilia and what mechanisms, specifically complement activation, might contribute to its occurrence. In 48 patients, eosinophil counts and concentrations of complement activation products, such as C3a, C5a, and sC5b-9, interleukin (IL)-5, and IL-6 in PDF were evaluated on days 1, 2, and 4 after starting PD therapy. We focused on the relationships between patient background characteristics and eosinophil counts and levels of C3a, C5a, and sC5b-9 as complement activation products in PDF. In 33.3% of PD patients, increased PDF eosinophils were observed on day 1. Eosinophil counts correlated with PDF levels of C3a on days 1 and 2, IL-5 on days 1, 2, and 4, and IL-6 on day 1. In terms of background characteristics, only the duration the PD catheter was left in place differed significantly between PDF eosinophilia and non-PDF eosinophilia. Notably, PDF levels of C3a differed significantly between patients with and without eosinophilia, suggesting that C3a might be a candidate for induction of increased eosinophil. PDF eosinophilia was frequently observed during PD initiation. Our results suggest that PD catheter insertion and complement activation might be related to increases in eosinophils in PDF during PD initiation.
8
Mycroft, Katarzyna, Magdalena Paplińska-Goryca, Małgorzata Proboszcz, Patrycja Nejman-Gryz, Rafał Krenke, and Katarzyna Górska. "Blood and Sputum Eosinophils of COPD Patients Are Differently Polarized than in Asthma." Cells 12, no. 12 (June 15, 2023): 1631. http://dx.doi.org/10.3390/cells12121631.
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Different eosinophil subpopulations have been identified in asthma and other eosinophilic disorders. However, there is a paucity of data on eosinophil subpopulations in patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to compare eosinophil phenotypes in blood and induced sputum in patients with COPD, asthma and controls. Stable patients with mild-to-moderate COPD (n = 15) and asthma (n = 14) with documented blood eosinophilia ≥100 cells/µL in the year prior to the study and the control group (n = 11) were included to the study. The blood and sputum eosinophil phenotypes were analyzed by flow cytometry. IL-5, IL-13, CCL5 and eotaxin-3 levels were measured in the induced sputum. The marker expression on blood eosinophils was similar among control, asthma and COPD groups. The expressions of CD125, CD193, CD14 and CD62L were higher on blood than on sputum eosinophils in all three groups. We found increased levels of CD193+ and CD66b+ sputum eosinophils from COPD patients, and an elevated level of CD11b+ sputum eosinophils in asthma compared to COPD patients. The results of our study suggest that the profile of marker expression on COPD sputum eosinophils differed from other groups, suggesting a distinct phenotype of eosinophils of COPD patients than in asthma or healthy subjects.
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Kiani, Arda, Fatemehsadat Rahimi, Siamak Afaghi, Maryam Paat, Mohammad Varharam, Mehdi Kazempour Dizaji, Maryam Dastoorpoor, and Atefeh Abedini. "Association of Upon-Diagnosis Blood Eosinophilic Count with Frequency and Severity of Annual Exacerbation in Chronic Obstructive Pulmonary Disease: A Prospective Longitudinal Analysis." Canadian Respiratory Journal 2023 (April 26, 2023): 1–11. http://dx.doi.org/10.1155/2023/8678702.
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Introduction. There is a controversy regarding the relationship between blood eosinophil count and COPD exacerbation. We aimed to determine whether peripheral eosinophils upon COPD diagnosis could affect the frequency and severity of annual acute exacerbation of COPD (AECOPD). Methods. This prospective study was conducted on 973 newly diagnosed COPD patients who were under 1-year follow-up in a pulmonology center in Iran. The Cox proportional model, polynomial regression, and receiver operator characteristic curves were conducted to evaluate the impact of the eosinophil levels on AECOPD. A linear regression model was conducted to evaluate the continuous association of eosinophilic count with AECOPDs. Results. Patients with eosinophil >200 cells/microliter were higher pack-year smokers with more pulmonary hypertension prevalence compared to COPD patients with <200 cells/microliter. There was a positive correlation between the eosinophilic count and the frequency of AECOPDs. Eosinophil >900 cells/microliter and eosinophil >600 cells/microliter had a sensitivity of 71.1% and 64.3%, respectively, in predicting the occurrence of more than one AECOPD. Eosinophilic count cutoff of 800 cells/microliter had the highest Youden index with sensitivity and specificity of 80.2% and 76.6%, respectively, for incident AECOPD in newly diagnosed patients. Using a linear model, increasing 180 cells/microliter in serum eosinophils was associated with further exacerbation. Evaluating gender, BMI, smoking pack-year, FEV1/FVC, CAT score, GOLD score, pulmonary hypertension, annual influenza, pneumococcal vaccinations, leukocytosis, and blood eosinophils, only blood eosinophils (hazard ratio (HR) = 1.44; 95% confidence interval = 1.33–2.15; p value = 0.03) and GOLD score (HR = 1.19; 95% CI = 1.30–1.52; p value = 0.03) were found as independent risk factors of AECOPD >3 episodes/year. Requirement for ICU admission, invasive ventilation, and mortality rate due to AECOPDs was similar between eosinophilic and noneosinophilic groups. Conclusion. Eosinophilia upon COPD diagnosis is a factor of recurrent AECOPDs. To reduce the risk of AECOPDs and the burden of disease, clinicians may consider inhaler corticosteroids and domiciliary oxygen with a lower threshold for eosinophilic-COPD patients regardless of their clinical status.
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Aldebert, D., B. Lamkhioued, C. Desaint, AS Gounni, M. Goldman, A. Capron, L. Prin, and M. Capron. "Eosinophils express a functional receptor for interferon alpha: inhibitory role of interferon alpha on the release of mediators." Blood 87, no. 6 (March 15, 1996): 2354–60. http://dx.doi.org/10.1182/blood.v87.6.2354.bloodjournal8762354.
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Recent reports describe the beneficial use of alpha interferon (IFNalpha) for the treatment of idiopathic hypereosinophilic syndrome (HES) unresponsive to conventional therapy. A clinical improvement associated with a rapid decrease of peripheral blood eosinophilia suggested possible direct effects of IFNalpha on eosinophils through the presence of IFNalpha receptors (IFNalphaR). Reverse transcriptase- polymerase chain reaction (RT-PCR) and cytochemistry were used respectively to detect the presence and define the distribution of IFNalphaR on enriched eosinophil preparations purified from blood cells. IFNalphaR was found on eosinophils collected from patients with various eosinophilic disorders. In addition, IFNalpha inhibited the release of eosinophil granule proteins such as eosinophil cationic protein (ECP), neurotoxin (EDN, or interleukin-5 (IL-5). Moreover, antiparasite cytotoxicity was also strongly reduced in a dose-dependent manner by IFNalpha. These results provide the first evidence that human eosinophils express a functional receptor for IFNalpha and represent a potential basis for the beneficial effects of IFNalpha in patients with hypereosinophilic syndromes.
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Masterson, Joanne C., Calies Menard-Katcher, Leigha D. Larsen, Glenn T. Furuta, and Lisa A. Spencer. "Heterogeneity of Intestinal Tissue Eosinophils: Potential Considerations for Next-Generation Eosinophil-Targeting Strategies." Cells 10, no. 2 (February 17, 2021): 426. http://dx.doi.org/10.3390/cells10020426.
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Eosinophils are implicated in the pathophysiology of a spectrum of eosinophil-associated diseases, including gastrointestinal eosinophilic diseases (EGIDs). Biologics that target the IL-5 pathway and are intended to ablate eosinophils have proved beneficial in severe eosinophilic asthma and may offer promise in treating some endotypes of EGIDs. However, destructive effector functions of eosinophils are only one side of the coin; eosinophils also play important roles in immune and tissue homeostasis. A growing body of data suggest tissue eosinophils represent a plastic and heterogeneous population of functional sub-phenotypes, shaped by environmental (systemic and local) pressures, which may differentially impact disease outcomes. This may be particularly relevant to the GI tract, wherein the highest density of eosinophils reside in the steady state, resident immune cells are exposed to an especially broad range of external and internal environmental pressures, and greater eosinophil longevity may uniquely enrich for co-expression of eosinophil sub-phenotypes. Here we review the growing evidence for functional sub-phenotypes of intestinal tissue eosinophils, with emphasis on the multifactorial pressures that shape and diversify eosinophil identity and potential targets to inform next-generation eosinophil-targeting strategies designed to restrain inflammatory eosinophil functions while sustaining homeostatic roles.
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Rothenberg, Marc E., James A. MacLean, Eric Pearlman, Andrew D. Luster, and Philip Leder. "Targeted Disruption of the Chemokine Eotaxin Partially Reduces Antigen-induced Tissue Eosinophilia." Journal of Experimental Medicine 185, no. 4 (February 17, 1997): 785–90. http://dx.doi.org/10.1084/jem.185.4.785.
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The chemokines are a large group of chemotactic cytokines that regulate leukocyte trafficking and have recently been shown to inhibit human immunodeficiency virus entry into cells. Eotaxin is a C–C chemokine implicated in the recruitment of eosinophils in a variety of inflammatory disorders and, unlike all other eosinophil chemoattractants, is eosinophil specific. However, given the large number of chemoattractants that have activities on eosinophils, it is unclear whether eotaxin has an important role in vivo. Furthermore, it remains unclear why there is constitutive expression of eotaxin in healthy states in the absence of eosinophilic inflammation. To begin to determine the significance of eotaxin at baseline and during eosinophil-mediated disease processes, we have used targeted gene disruption to generate mice that are deficient in eotaxin. Such mice demonstrate that eotaxin enhances the magnitude of the early (but not late) eosinophil recruitment after antigen challenge in models of asthma and stromal keratitis. Surprisingly, a role for eotaxin in regulating the constitutive number of eosinophils in the peripheral circulation is also demonstrated. These results indicate a contributory role for eotaxin in the generation of peripheral blood and antigen-induced tissue eosinophilia.
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Balla, Keir M., Geanncarlo Lugo-Villarino, Jan M. Spitsbergen, David L. Stachura, Yan Hu, Karina Bañuelos, Octavio Romo-Fewell, Raffi V. Aroian, and David Traver. "Eosinophils in the zebrafish: prospective isolation, characterization, and eosinophilia induction by helminth determinants." Blood 116, no. 19 (November 11, 2010): 3944–54. http://dx.doi.org/10.1182/blood-2010-03-267419.
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Abstract Eosinophils are granulocytic leukocytes implicated in numerous aspects of immunity and disease. The precise functions of eosinophils, however, remain enigmatic. Alternative models to study eosinophil biology may thus yield novel insights into their function. Eosinophilic cells have been observed in zebrafish but have not been thoroughly characterized. We used a gata2:eGFP transgenic animal to enable prospective isolation and characterization of zebrafish eosinophils, and demonstrate that all gata2hi cells in adult hematopoietic tissues are eosinophils. Although eosinophils are rare in most organs, they are readily isolated from whole kidney marrow and abundant within the peritoneal cavity. Molecular analyses demonstrate that zebrafish eosinophils express genes important for the activities of mammalian eosinophils. In addition, gata2hi cells degranulate in response to helminth extract. Chronic exposure to helminth- related allergens resulted in profound eosinophilia, demonstrating that eosinophil responses to allergens have been conserved over evolution. Importantly, infection of adult zebrafish with Pseudocapillaria tomentosa, a natural nematode pathogen of teleosts, caused marked increases in eosinophil number within the intestine. Together, these observations support a conserved role for eosinophils in the response to helminth antigens or infection and provide a new model to better understand how parasitic worms activate, co-opt, or evade the vertebrate immune response.
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Sehmi, R., AJ Wardlaw, O. Cromwell, K. Kurihara, P. Waltmann, and AB Kay. "Interleukin-5 selectively enhances the chemotactic response of eosinophils obtained from normal but not eosinophilic subjects." Blood 79, no. 11 (June 1, 1992): 2952–59. http://dx.doi.org/10.1182/blood.v79.11.2952.2952.
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Abstract We have attempted to determine whether interleukin-5 (IL-5), a cytokine that selectively affects eosinophil (as opposed to neutrophil) differentiation and activation, also modulates eosinophil migrational responses. Using a modified Boyden chemotaxis assay, IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) gave a weak locomotory response for eosinophils from normal nonatopic subjects (optimal at 10(-11), 10(-8), and 10(-9) mol/L, respectively), but not for eosinophils from subjects with an eosinophilia associated with asthma and/or allergic rhinitis. In contrast, IL-5 and IL-3 had no effect on neutrophils, while GM-CSF was chemotactic for neutrophils over a limited concentration range, optimal at 10(-8) mol/L. When eosinophils from normal subjects were incubated with IL-5 (10(-9) mol/L), the locomotory response to platelet-activating factor (PAF; 10(- 8) mol/L, P less than .05), leukotriene B4 (LTB4; 10(-6) mol/L, P less than .01), and N-formyl-methionyl-leucyl-phenylalanine (FMLP; 10(-8) mol/L, P less than .01) was significantly enhanced. The percentage enhancement of eosinophil locomotion by IL-5 was greater for eosinophils from normal as compared with subjects with an eosinophilia associated with asthma (P less than .05 for PAF and LTB4; P less than .01 for FMLP). Preincubation of eosinophils from normal subjects with IL-5 (10(-9) mol/L) attenuated the subsequent locomotory response to IL- 5 (10(-12) and 10(-11) mol/L, P less than .05). Therefore, the observed refractoriness of eosinophils from eosinophilic subjects to both directional migratory and priming effects of IL-5 in vitro, may reflect a deactivation process resulting from prior exposure in vivo. The selective priming of eosinophil but not neutrophil locomotion by IL-5 suggests that this cytokine may play a significant role in the preferential accumulation of eosinophils at sites of allergic inflammation.
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Sehmi, R., AJ Wardlaw, O. Cromwell, K. Kurihara, P. Waltmann, and AB Kay. "Interleukin-5 selectively enhances the chemotactic response of eosinophils obtained from normal but not eosinophilic subjects." Blood 79, no. 11 (June 1, 1992): 2952–59. http://dx.doi.org/10.1182/blood.v79.11.2952.bloodjournal79112952.
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We have attempted to determine whether interleukin-5 (IL-5), a cytokine that selectively affects eosinophil (as opposed to neutrophil) differentiation and activation, also modulates eosinophil migrational responses. Using a modified Boyden chemotaxis assay, IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) gave a weak locomotory response for eosinophils from normal nonatopic subjects (optimal at 10(-11), 10(-8), and 10(-9) mol/L, respectively), but not for eosinophils from subjects with an eosinophilia associated with asthma and/or allergic rhinitis. In contrast, IL-5 and IL-3 had no effect on neutrophils, while GM-CSF was chemotactic for neutrophils over a limited concentration range, optimal at 10(-8) mol/L. When eosinophils from normal subjects were incubated with IL-5 (10(-9) mol/L), the locomotory response to platelet-activating factor (PAF; 10(- 8) mol/L, P less than .05), leukotriene B4 (LTB4; 10(-6) mol/L, P less than .01), and N-formyl-methionyl-leucyl-phenylalanine (FMLP; 10(-8) mol/L, P less than .01) was significantly enhanced. The percentage enhancement of eosinophil locomotion by IL-5 was greater for eosinophils from normal as compared with subjects with an eosinophilia associated with asthma (P less than .05 for PAF and LTB4; P less than .01 for FMLP). Preincubation of eosinophils from normal subjects with IL-5 (10(-9) mol/L) attenuated the subsequent locomotory response to IL- 5 (10(-12) and 10(-11) mol/L, P less than .05). Therefore, the observed refractoriness of eosinophils from eosinophilic subjects to both directional migratory and priming effects of IL-5 in vitro, may reflect a deactivation process resulting from prior exposure in vivo. The selective priming of eosinophil but not neutrophil locomotion by IL-5 suggests that this cytokine may play a significant role in the preferential accumulation of eosinophils at sites of allergic inflammation.
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Diny, Nicola, Jobert G. Barin, Monica Talor, Noel R. Rose, and Daniela Cihakova. "Eosinophil-derived IL-4 drives inflammatory dilated cardiomyopathy." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 207.7. http://dx.doi.org/10.4049/jimmunol.198.supp.207.7.
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Abstract Inflammatory dilated cardiomyopathy (DCM) is a major cause of heart failure in children and young adults. DCM develops in up to 30% of myocarditis patients, but the mechanisms involved in disease progression are poorly understood. Patients with eosinophilia frequently develop cardiomyopathies. We determined the role of eosinophils in myocarditis and DCM using the experimental autoimmune myocarditis (EAM) model. In wildtype (WT) BALB/c mice, EAM progresses to DCM and heart failure. Eosinophil-deficient ΔdblGATA1 mice developed myocarditis but showed no signs of heart failure. Thus, eosinophils were dispensable for myocarditis induction but required for progression to DCM. EAM in hypereosinophilic IL5Tg mice resulted in eosinophilic myocarditis with severe atrial inflammation and progressed to severe DCM. Atrial inflammation was also observed in 2 of 3 patients with eosinophilic myocarditis. The DCM phenotype required eosinophils but not IL5. IL5TgΔdblGATA1 mice were protected from DCM while IL5−/− mice exhibited DCM comparable to WT mice. Eosinophils drove progression to DCM through their production of IL4. In our experiments, eosinophils were the major IL4 expressing cell type in the heart during EAM. Like ΔdblGATA1 mice, IL4−/− mice were protected from DCM and eosinophil-specific IL4 deletion resulted in improved heart function. In conclusion, eosinophils drive progression of myocarditis to DCM, cause severe DCM when present in large numbers, and mediate this process through IL4.
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Citgez, Emanuel, Job van der Palen, Paul van der Valk, Huib A. M. Kerstjens, and Marjolein Brusse-Keizer. "Stability in eosinophil categorisation during subsequent severe exacerbations of COPD." BMJ Open Respiratory Research 8, no. 1 (August 2021): e000960. http://dx.doi.org/10.1136/bmjresp-2021-000960.
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BackgroundThe blood eosinophil count has been shown to be a promising biomarker for establishing personalised treatment strategies to reduce corticosteroid use, either inhaled or systemic, in chronic obstructive pulmonary disease (COPD). Eosinophil levels seem relatively stable over time in stable state, but little is known whether this is also true in subsequent severe acute exacerbations of COPD (AECOPD).Aims and objectivesTo determine the stability in eosinophil categorisation between two subsequent severe AECOPDs employing frequently used cut-off levels.MethodsDuring two subsequent severe AECOPDs, blood eosinophil counts were determined at admission to the hospital in 237 patients in the Cohort of Mortality and Inflammation in COPD Study. The following four cut-off levels were analysed: absolute counts of eosinophils ≥0.2×10⁹/L (200 cells/µL) and ≥0.3×10⁹/L (300 cells/µL) and relative eosinophil percentage of ≥2% and ≥3% of total leucocyte count. Categorisations were considered stable if during the second AECOPD their blood eosinophil status led to the same classification: eosinophilic or not.ResultsDepending on the used cut-off, the overall stability in eosinophil categorisation varied between 70% and 85% during two subsequent AECOPDs. From patients who were eosinophilic at the first AECOPD, 34%–45% remained eosinophilic at the subsequent AECOPD, while 9%–21% of patients being non-eosinophilic at the first AECOPD became eosinophilic at the subsequent AECOPD.ConclusionsThe eosinophil variability leads to category changes in subsequent AECOPDs, which limits the eosinophil categorisation stability. Therefore, measurement of eosinophils at each new exacerbation seems warranted.
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Ackerman, S. J., G. M. Kephart, H. Francis, K. Awadzi, G. J. Gleich, and E. A. Ottesen. "Eosinophil degranulation. An immunologic determinant in the pathogenesis of the Mazzotti reaction in human onchocerciasis." Journal of Immunology 144, no. 10 (May 15, 1990): 3961–69. http://dx.doi.org/10.4049/jimmunol.144.10.3961.
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Abstract Onchocerciasis patients treated with diethylcarbamazine often undergo a severe inflammatory response, the Mazzotti reaction. To assess the eosinophil's role in the pathogenesis of the Mazzotti reaction, we obtained serial blood, plasma, and skin biopsy specimens from 21 heavily infected patients and 3 endemic controls, both before and during therapy with diethylcarbamazine. Samples were analyzed for blood eosinophils, plasma levels of eosinophil granule major basic protein (MBP) and eosinophil-derived neurotoxin, eosinophil infiltration and eosinophil and mast cell degranulation in the skin. After the first dose of diethylcarbamazine, blood eosinophils fell from a pre-treatment level of 888 +/- 111 to 203 +/- 42 cells/mm3 at 8 h. This decrease was followed by a marked eosinophilia developing over the remaining 7 days of treatment and 14 days of follow-up. Plasma eosinophil-derived neurotoxin levels increased from 56 +/- 4 ng/ml pretreatment to a peak of 82 +/- 9 ng/ml at 8 h and returned to pretreatment levels by 48 h. Beginning at 12 h, plasma MBP levels increased from 730 +/- 74 ng/ml pretreatment to a peak of 1140 +/- 74 ng/ml after 5 days. Pretreatment skin biopsies stained for MBP by immunofluorescence showed a bright fibrillar pattern in the dermis consistent with chronic eosinophil degranulation; the MBP was localized on elastic tissue fibers. After treatment, skin biopsy specimens showed both the pretreatment fibrillar MBP staining pattern as well as focal eosinophil degranulation. Deposition of MBP around microfilariae in the papillary dermis was visible as early as 1.5 h. The lowest blood eosinophil levels and peak plasma eosinophil-derived neurotoxin levels coincided with the infiltration and degranulation of eosinophils in the skin. Mast cell degranulation in the skin was maximal by the first posttreatment biopsy (1.5 h) coincident with the beginning of eosinophil degranulation. Although the pathogenesis of the Mazzotti reaction is clearly complex, our results indicate that eosinophil degranulation is characteristic of the response and that it occurs with a time course suggestive of a role for the eosinophil in determining the clinical and pathologic manifestations of the reaction.
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Shamri, Revital, Kristen Young, and Peter Weller. "p38 MAPK but not ERK is required for eosinophil migration and degranulation (172.29)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 172.29. http://dx.doi.org/10.4049/jimmunol.188.supp.172.29.
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Abstract Eosinophil-associated RNases (EARs); the human eosinophil-derived neurotoxin and eosinophilic cationic protein and their murine orthologs, are stored in eosinophil cytoplasmic granules and secreted upon inflammation as part of innate immune responses. In eosinophil-associated diseases, such as hyper eosinophilic syndrome, allergy and asthma, EARs play crucial roles in disease pathology and can be used as biomarkers for disease severity. However, secretion mechanisms of EARs are not fully understood, especially in mouse eosinophils, the major animal model for eosinophil-associated diseases. Our study aimed to understand the mechanisms of eosinophil EAR secretion following chemokine stimulation. Both ERK and p38 MAPK activation were found to increase in mouse eosinophils in response to CCL11. CCR3-mediated EAR secretion was blocked by p38 inhibitor (SB202190), confirming previous data in human eosinophils. However, a specific inhibitor for ERK, a MEK1-derived peptide, did not inhibit CCR3-mediated secretion or migration. These results are in contrast to previous studies in human eosinophils and our studies in mouse eosinophils, showing ERK is crucial for CCR3-mediated EARs secretion and migration using PD98059, a less specific inhibitor of the ERK-activating enzyme, MEK. Collectively, these data suggest a signaling pathway for CCR3-mediated EAR secretion that includes: PI3K and p38 but not ERK. These findings are pertinent to host defense and eosinophil-associated diseases.
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Manohar, Murli, Alok K. Verma, Sathisha Upparahalli Venkateshaiah, and Anil Mishra. "Role of eosinophils in the initiation and progression of pancreatitis pathogenesis." American Journal of Physiology-Gastrointestinal and Liver Physiology 314, no. 2 (February 1, 2018): G211—G222. http://dx.doi.org/10.1152/ajpgi.00210.2017.
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Eosinophilic pancreatitis (EP) is reported in humans; however, the etiology and role of eosinophils in EP pathogenesis are poorly understood and not well explored. Therefore, it is interesting to examine the role of eosinophils in the initiation and progression of pancreatitis pathogenesis. Accordingly, we performed anti-major basic protein immunostaining, chloroacetate esterase, and Masson’s trichrome analyses to detect eosinophils, mast cells, and collagen in the tissue sections of mouse and human pancreas. Induced eosinophils accumulation and degranulation were observed in the tissue sections of human pancreatitis, compared with no eosinophils in the normal pancreatic tissue sections. Similarly, we observed induced tissue eosinophilia along with mast cells and acinar cells atrophy in cerulein-induced mouse model of chronic pancreatitis. Additionally, qPCR and ELISA analyses detected induced transcript and protein levels of proinflammatory and profibrotic cytokines, chemokines like IL 5, IL-18, eotaxin-1, eotaxin-2, TGF-β1, collagen-1, collagen-3, fibronectin, and α-SMA in experimental pancreatitis. Mechanistically, we show that eosinophil-deficient GATA1 and endogenous IL-5-deficient mice were protected from the induction of proinflammatory and profibrotic cytokines, chemokines, tissue eosinophilia, and mast cells in a cerulein-induced murine model of pancreatitis. These human and experimental data indicate that eosinophil accumulation and degranulation may have a critical role in promoting pancreatitis pathogenesis including fibrosis. Taken together, eosinophil tissue accumulation needs appropriate attention to understand and restrict the progression of pancreatitis pathogenesis in humans.NEW & NOTEWORTHY The present study for the first time shows that eosinophils accumulate in the pancreas and promote disease pathogenesis, including fibrosis in earlier reported cerulein-induced experimental models of pancreatitis. Importantly, we show that GATA-1 and IL-5 deficiency protects mice form the induction of eosinophil active chemokines, and profibrotic cytokines, including accumulation of tissue collagen in an experimental model of pancreatitis. Additionally, we state that cerulein-induced chronic pancreatitis is independent of blood eosinophilia.
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Radke, Amy L., Lauren E. Reynolds, Rossana C. N. Melo, Ann M. Dvorak, Peter F. Weller, and Lisa A. Spencer. "Mature human eosinophils express functional Notch ligands mediating eosinophil autocrine regulation." Blood 113, no. 13 (March 26, 2009): 3092–101. http://dx.doi.org/10.1182/blood-2008-05-155937.
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Abstract Eosinophil chemotaxis and survival within tissues are key components in the development of tissue eosinophilia and subsequent effector responses. In this study, we demonstrate a novel mechanism of eosinophil autoregulation affecting migration and survival mediated through Notch signaling. We show for the first time that human blood eosinophils express Notch receptors and Notch ligands, expressions of which are influenced by the presence of eosinophil-activating granulocyte-macrophage colony-stimulating factor (GM-CSF). Evidence of Notch receptor activation and subsequent transcription of the Notch-responsive gene HES1 were observed in GM-CSF–stimulated eosinophils, confirming functionality of eosinophil-expressed Notch-signaling components. Moreover, by inhibiting Notch signaling with γ-secretase inhibitors or Notch receptor–specific neutralizing antibodies, we demonstrate that autocrine Notch signaling enhances stimulus-mediated actin rearrangement and eosinophil chemokinesis, and impairs eosinophil viability. Taken together, these data suggest autocrine Notch signaling, enhanced in response to tissue- or inflammatory-derived signals, influences eosinophil activity and longevity, which may ultimately contribute to the development of tissue eosinophilia and exacerbation or remediation of eosinophil effector functions.
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Hiraoka, Tomoko, Ngo Chi Cuong, Sugihiro Hamaguchi, Mihoko Kikuchi, Shungo Katoh, Le Kim Anh, Nguyen Thi Hien Anh, et al. "Meningitis patients with Angiostrongylus cantonensis may present without eosinophilia in the cerebrospinal fluid in northern Vietnam." PLOS Neglected Tropical Diseases 14, no. 12 (December 22, 2020): e0008937. http://dx.doi.org/10.1371/journal.pntd.0008937.
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Background Eosinophilic meningitis (EM) is a rare clinical syndrome caused by both infectious and noninfectious diseases. In tropical pacific countries, Angiostrongylus cantonensis is the most common cause. However, the EM definition varies in the literature, and its relation to parasitic meningitis (PM) remains unclear. Methodology/Principal findings Adult and adolescent patients of 13 years old or above with suspected central nervous system (CNS) infections with abnormal CSF findings were prospectively enrolled at a tertiary referral hospital in Hanoi, Vietnam from June 2012 to May 2014. Patients with EM or suspected PM (EM/PM) were defined by the presence of either ≥10% eosinophils or an absolute eosinophil cell counts of ≥10/mm3 in the CSF or blood eosinophilia (>16% of WBCs) without CSF eosinophils. In total 679 patients were enrolled: 7 (1.03%) had ≥10% CSF eosinophilia, 20 (2.95%) had ≥10/mm3 CSF eosinophilia, and 7 (1.03%) had >16% blood eosinophilia. The patients with ≥10% CSF eosinophilia were significantly younger (p = 0.017), had a lower body temperature (p = 0.036) than patients with ≥10/mm3 CSF eosinophilia among whom bacterial pathogens were detected in 72.2% (13/18) of those who were tested by culture and/or PCR. In contrast, the characteristics of the patients with >16% blood eosinophilia resembled those of patients with ≥10% CSF eosinophilia. We further conducted serological tests and real-time PCR to identify A. cantonensis. Serology or real-time PCR was positive in 3 (42.8%) patients with ≥10% CSF eosinophilia and 6 (85.7%) patients with >16% blood eosinophilia without CSF eosinophils but none of patients with ≥10/mm3 CSF eosinophilia. Conclusions The etiology of PM in northern Vietnam is A. cantonensis. The eosinophil percentage is a more reliable predictor of parasitic EM than absolute eosinophil count in the CSF. Patients with PM may present with a high percentage of eosinophils in the peripheral blood but not in the CSF.
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Jain, Megha, Sowmya Kasetty, U. S. Sudheendra, Manisha Tijare, Samar Khan, and Ami Desai. "Assessment of Tissue Eosinophilia as a Prognosticator in Oral Epithelial Dysplasia and Oral Squamous Cell Carcinoma—An Image Analysis Study." Pathology Research International 2014 (February 19, 2014): 1–6. http://dx.doi.org/10.1155/2014/507512.
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Association of tissue eosinophilia with oral squamous cell carcinoma has shown variable results ranging from favourable to unfavourable or even having no influence on prognosis. Also, very few studies have been done to know the role of eosinophils in premalignancy. So the present study investigated role of eosinophilic infiltration in oral precancer and cancer and its possible use as a prognosticator. 60 histopathologically proven cases (20 cases each of metastatic and nonmetastatic oral squamous cell carcinoma and oral leukoplakia with dysplasia of various grades) were included. Congo red is used as a special stain for eosinophils. Each specimen slide was viewed under high power in 10 consecutive microscopic fields for counting of eosinophils. As a result, a significant increase in eosinophil count was found in oral carcinomas compared to dysplasia. Nonmetastatic cases showed higher counts than metastatic carcinomas. So, it is concluded that eosinophilia is a favourable histopathological prognostic factor in oral cancer. Moreover, higher eosinophil counts in carcinoma group compared to dysplasia group proved that they might have a role in stromal invasion thus suggesting that quantitative assessment of tissue eosinophilia should become a part of the routine histopathological diagnosis for oral precancer and OSCC.
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Okafor, Ndubuisi C., Ayodeji A. Oso, Amanke C. Oranu, Steven M. Wolff, and John J. Murray. "Eosinophilic Pleural Effusion: A Rare Manifestation of Hypereosinophilic Syndrome." Case Reports in Medicine 2009 (2009): 1–3. http://dx.doi.org/10.1155/2009/635309.
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Several causes of eosinophilic pleural effusions have been described with malignancy being the commonest cause. Hypereosinophilic syndrome (HES) is a rare disease and very few cases have been reported of HES presenting as eosinophilic pleural effusion (EPE). We report a case of a 26-year-old male who presented with shortness of breath. He had bilateral pleural effusions, generalized lymphadenopathy, splenomegaly, and leukocytosis with marked peripheral blood eosinophilia. The pleural fluid was exudative, with 25%–30% eosinophilis, and absence of neoplastic cells. Hypereosinophilic syndrome was diagnosed after other causes of eosinophilia were excluded. He continued to be dyspneic with persistent accumulation of eosinophilic pleural fluid, even after his peripheral eosinophil count had normalized in response to treatment. This patient represents a very unusual presentation of HES with dyspnea and pleural effusions and demonstrates that treatment based on response of peripheral eosinophil counts, as is currently recommended, may not always be clinically adequate.
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Ganti, Ashwin, Hannah N. Kuhar, Michael Eggerstedt, Mahboobeh Mahdavinia, Paolo Gattuso, Pete S. Batra, and Bobby A. Tajudeen. "The Association of Serum Eosinophilia with Structured Histopathology in Chronic Rhinosinusitis." Annals of Otology, Rhinology & Laryngology 129, no. 5 (December 30, 2019): 512–16. http://dx.doi.org/10.1177/0003489419898200.
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Background: Prior studies have demonstrated associations between serum eosinophilia and chronic rhinosinusitis (CRS) pathogenesis. However, the association of serum eosinophilia with histopathology profiling in CRS has not been fully delineated and may help better characterize CRS disease burden prior to surgery. Methods: A structured histopathology report of 13 variables was utilized to analyze sinus tissue removed during functional endoscopic sinus surgery (FESS). Complete blood count (CBC) with differential was drawn within 4 weeks prior to FESS. Serum eosinophilia was defined as >6.0% (>0.60 th/μL). Histopathology variables were compared among patients. Results: A total of 177 CRS patients (37 with serum eosinophilia and 140 with normal serum eosinophilia) were analyzed. Compared to CRS patients with normal serum eosinophil counts, CRS patients with serum eosinophilia demonstrated increased polypoid disease (67.6% vs 35.0%, P < .001), eosinophil aggregates (45.9% vs 20.7%, P = .003), and eosinophils per high-power field (>5/HPF) (67.6% vs 40.7%, P = .003). Conclusion: CRS patients with serum eosinophilia demonstrated severe disease burden on histopathology with high levels of polypoid disease and tissue eosinophilia. However, a considerable number of patients without serum eosinophilia demonstrated eosinophilic disease on histopathology, indicating that preoperative serum eosinophilia alone could not be reliably used to predict eosinophilic CRS. Level of evidence: 4
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Liu, Wenlong, Qingxiang Zeng, Yanqiu Chen, and Ren Zhong Luo. "Role of Leptin/Osteopontin Axis in the Function of Eosinophils in Allergic Rhinitis with Obesity." Mediators of Inflammation 2018 (October 24, 2018): 1–10. http://dx.doi.org/10.1155/2018/9138904.
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Background. Allergic rhinitis (AR) is characterized by tissue and blood eosinophilia. Previous studies showed enhanced eosinophilia in allergic rhinitis patients with obesity, suggesting an association between obesity and eosinophilia. However, the interaction and mechanism between obesity and eosinophilia is still unclear. Methods. We recruited thirty AR children and 30 controls in this study. Expression of leptin and osteopontin (OPN) proteins in serum was detected, and correlation analysis with eosinophilia was performed. The effect of leptin or OPN on eosinophil apoptosis, adhesion, migration, and activation of eosinophil was examined. Ovalbumin-sensitized mice were established to prove the role of obesity on eosinophil regulation by leptin and OPN. Results. We found that upregulated serum and nasal leptin and OPN expression in AR were positively correlated with eosinophilia and eosinophil cationic protein levels. Leptin or OPN inhibited eosinophil apoptosis, demonstrated as inhibited DNA fragmentation and phosphatidylserine (PS) redistribution (P<0.05). Leptin and OPN promote expression of cluster of differentiation 18 (CD-18) and intercellular adhesion molecule 1 (ICAM-1) and inhibit expression of ICAM-1 and L-selectin by eosinophils, which contribute to the adhesion of eosinophils. Leptin and OPN mediated migration and activation of eosinophil through phosphatidylinositol-3-OH kinase (PI3K) pathway. Obese AR mice presented with more severe eosinophilia and symptoms compared with nonobese AR mice or control mice. Immunochemistry staining of leptin and OPN of nasal turbinate in obese AR mice was also stronger than those in nonobese AR mice or control mice. Anti-OPN, anti-leptin, and anti-α4 treatments reduce nasal eosinophilia inflammation and clinical symptoms in model mice. Conclusion. Our results suggested that in an obese state, upregulation of leptin and OPN regulates apoptosis, adhesion, migration, and activation of eosinophils, and this process may be mediated by the PI3K and anti-α4 pathways.
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Lykkegaard Andersen, Christen, Volkert Siersma, Hanne Vestergaard, Peter Felding, Hans Carl Hasselbalch, Niels de Fine Olivarius, and Ole Weis Bjerrum. "Risks of Eosinophil-Related End-Organ Damage, Hematological Malignancies and Death Are Significantly Increased Even below Consensus Threshold Criteria for Blood Eosinophilia." Blood 122, no. 21 (November 15, 2013): 2831. http://dx.doi.org/10.1182/blood.v122.21.2831.2831.
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Abstract Introduction Blood eosinophilia may arise from clonal intrinsic disorders or reactive extrinsic conditions. The eosinophilic granulocytes (eosinophils) may have diverse physiological functions and cause organ involvement. A dose-dependent relation between eosinophilia and risks of end-organ damage has not been described and it is not known whether numbers below internationally used threshold criteria for eosinophilia in adults (<0.5x109/L) may pose increased risks of eosinophil-related outcomes. Also, eosinophilia may represent an early paraclinical sign of hematological malignant disease (Andersen et al, Am J Hematol 2013), but the change in risks as a continuous function of the numbers of eosinophils has not been investigated. The aim of the study was, by the use of routine blood samples from a comprehensive primary care cohort, to investigate the effect of eosinophils on risks of experiencing end-organ damage and to explore the continuous functional form of the known effect on risks of hematological malignancies and death in search of prognostic cutoffs. Methods From the Copenhagen Primary Care Differential Count (CopDiff) database, we identified 359.950 individuals with at least one differential cell count (DIFF) from 2000-2007. From these, one DIFF was randomly chosen from each individual. From the Danish Cancer Registry and the Danish Civil Registration System we ascertained hematological malignancies and death within three years following the DIFF. From the Danish National Patient Register we ascertained cardiological, neurological, skin, gastrointestinal and respiratory disease within three years following the DIFF. Furthermore we computed Charlson's comorbidity Index (CCI) within three years before the DIFF. Using multivariate logistic regression, the odds ratio between the eosinophil count and the three-year incidence of the outcome was calculated as a restricted cubic spline (Desquilbet et al, Stat Med 2010) and adjusted for previous eosinophilia, sex, age, year, month, CRP, previous cancer and CCI. Results In the total cohort of 359.950 individuals from a primary care setting there was an equal sex-distribution and a mean age of 48.3 years. 345.544 individuals had eosinophils within the reference interval whereas 14.406 individuals (4%) exhibited eosinophilia. Risks for all outcomes were significantly increased above, but also below the consensus threshold criteria for eosinophilia. The lowest risk for hematologic cancer was found at an eosinophil count of 0.17 x109/L – which we set to be the baseline eosinophil count for all spline figures (figures 1-7). The lowest risk for benign disease and death was found at a similar eosinophil count. Risks for all outcomes increased for counts >0.17 x109/L and plateaued around 1.0x109/l. Risks for many outcomes also significantly increased for eosinophil counts < 0.17 x109/l up to a level of risk comparable to severe eosinophilia. Conclusion In this study on almost 400.000 individuals, we demonstrate that eosinophils may increase the risk of end-organ damage as well as malignant hematological disease and death even within the limits of consensus normal range. This observation possibly explains why a relationship between eosinophilia and organ damage or prognosis has been difficult to demonstrate previously. In the normal range below 0.17 x109/L a suspected phenomenon of extravasation is probable which converts to a prognostic factor for end-organ damage, death and hematological cancer which is also a novel observation. Apparently, a protective effect of low number of eosinophils in respiratory disease indicates that eosinophils may be causal in these disease entities and this needs to be investigated further. A plateau of ORs around 1x109/l has clinical impact for treating patients with primary eosinophilia because the risks of complications do not increase proportionally and suggests that in severe eosinophilia only a minor part of the eosinophil population leaves the blood stream to cause organ damage. More to be presented at ASH. Disclosures: No relevant conflicts of interest to declare.
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de Bruin, Alexander M., Miranda Buitenhuis, Koenraad F. van der Sluijs, Klaas P. J. M. van Gisbergen, Louis Boon, and Martijn A. Nolte. "Eosinophil differentiation in the bone marrow is inhibited by T cell–derived IFN-γ." Blood 116, no. 14 (October 7, 2010): 2559–69. http://dx.doi.org/10.1182/blood-2009-12-261339.
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Abstract To explore whether and how T cells can affect myelopoiesis, we investigated myeloid differentiation in a model for T cell-mediated immune activation. We found that CD70-transgenic (CD70TG) mice, which have elevated numbers of interferon-γ (IFN-γ)–producing effector T cells in the periphery and bone marrow, are almost devoid of eosinophilic granulocytes. Induction of allergic airway inflammation in these mice failed to induce eosinophilia as well as airway hyperresponsiveness. CD70TG mice also have strongly reduced numbers of eosinophil lineage-committed progenitors, whereas granulocyte/macrophage progenitors from these mice are unable to generate eosinophils in vitro. We found that granulocyte/macrophage progenitors express IFN-γR1 and that IFN-γ is sufficient to inhibit eosinophil differentiation of both murine and human progenitor cells in vitro. We demonstrate that inhibition of eosinophil development in CD70TG mice is IFN-γ–dependent and that T cell–derived IFN-γ is sufficient to inhibit eosinophil formation in vivo. Finally, we found that IFN-γ produced on anti-CD40 treatment and during viral infection can also suppress eosinophil formation in wild-type mice. These data demonstrate that IFN-γ inhibits the differentiation of myeloid progenitors to eosinophils, indicating that the adaptive immune system plays an important role in orchestrating the formation of the appropriate type of myeloid cells during immune activation.
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Mwanthi, Muithi, Gracie Michels, Karl Staser, Sarita Sehra, Michal Jander, Shi Chen, David S. Wilkes, Mark Kaplan, Su-jung Park, and D. Wade Clapp. "PAK1 Regulates Eotaxin-Mediated Murine Eosinophil Migration in Vitro and In Vivo." Blood 118, no. 21 (November 18, 2011): 18. http://dx.doi.org/10.1182/blood.v118.21.18.18.
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Abstract Abstract 18 Eosinophils are increasingly recognized as important myeloid effector cells in the inflammatory environment of many human diseases. Although eosinophils critically contribute to chronic asthmatic inflammation, few therapies directly target these cells. Eosinophils rapidly migrate to eotaxin elicited by allergic sensitization and challenge, a chemokine that ligates the CCR3 receptor. Eotaxin:CCR3 signaling critically regulates allergen-induced eosinophil infiltration in murine models by activating the Rho-family proteins. In several cell systems, the Rho proteins Rac and CDC42 activate p21-activated kinase 1 (PAK1), which we have previously shown to regulate F-actin dynamics and histamine release in the degranulating mast cell. In these studies, we examined eotaxin-induced eosinophil migration using genetic and hematopoietic ablation of Pak1 (Pak1−/−) in a murine asthma model. Using an in vitro transwell migration assay system, we evaluated the migration of bone marrow derived eosinophils of both genotypes to eotaxin (N=10). Pak1−/− eosinophils exhibited profoundly diminished eotaxin-induced chemotaxis in vitro relative to wild-type (Pak1+/+) eosinophils (p < 0.0001) with a 30% overall decrease in migrating Pak1−/− compared to Pak1+/+ eosinophils. Furthermore, we compared the eotaxin-induced localization and arrangement of F-actin in eosinophils of both genotypes by fluorescence cytometry and deconvolution confocal microscopy of fluorescently-tagged phalloidin in seeking to explain this migration defect. Preliminary findings suggest decreased F-actin polymerization in eotaxin-treated Pak1−/− eosinophils. In an independent line of experiments designed to compare eotaxin-mediated eosinophil recruitment in vivo we injected mice of both genotypes with an intraperitoneal dose of eotaxin or saline. Pak1+/+ mice showed an 8 fold eotaxin-mediated increase in eosinophil recruitment over control whereas Pak1−/− mice demonstrated only a modest 3–4 fold increase (p< 0.05). Finally we pursued PAK1's function in an experimental disease model in which the eosinophil's key role in pathogenesis is well documented. In 3 cohorts of 7 age, gender and strain matched Pak1+/+ and Pak1−/− ova albumin (OVA)-sensitized and challenged mice, we scored lung eosinophilic inflammation by histology and compared eosinophil counts and eotaxin concentrations in broncho-alveolar lavage fluid (BALF) by fluorescence cytometry and ELISA respectively. We also assessed OVA-specific T-cell subset cytokine secretion in our asthma mice by ELISA. Lung-parenchymal eosinophilic inflammation was diminished in Pak1−/− ova-sensitized mice versus Pak1+/+'s (p<0.01) with neither differences in BALF eotaxin content nor OVA-specific in vitro T-helper cell secretion of asthma-induced cytokines between the 2 genotypes. Based on our findings in this model, we assessed PAK1's hematopoietic role using two complementary chimeric mouse models. In a cohort of matched recipient Pak1+/+ mice we transplanted Pak1+/+ and Pak1−/− bone marrow and after hematopoietic reconstitution we incited asthmatic inflammation in these mice. Significantly, hosts transplanted with Pak1−/− bone marrow developed decreased eosinophilic inflammation scores compared to Pak1+/+ bone marrow recipients (p<0.05). To complement the bone marrow experiments, we transplanted left-lung grafts from Pak1+/+ and Pak1−/− mice into matched Pak1+/+ and Pak1−/− recipient mice and after surgical recuperation we elicited asthmatic inflammation as above. Similar to our bone marrow transplant experiments, irrespective of the genotype of the lung graft, hosts with Pak1−/− bone marrow developed decreased lung eosinophil infiltrate. Our data suggest that genetic PAK1 disruption hinders the in vitro and in vivo eotaxin-mediated migration of eosinophils by altering polymerization of F-actin. In an OVA murine model of asthma, we show that the genetic ablation of PAK1 attenuates the eosinophilic inflammation without affecting T-cell function. We similarly demonstrate that hematopoietic expression of PAK1 is critical to the development of eosinophil inflammation in two complementary transplant murine models. Pharmacologically targeting PAK1 may thus provide a specific way to impede eosinophil tissue infiltration, alleviate chronic eosinophil inflammation, and hamper long-term tissue remodeling in diseases like asthma. Disclosures: No relevant conflicts of interest to declare.
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Simon, H. U., S. Yousefi, C. Schranz, A. Schapowal, C. Bachert, and K. Blaser. "Direct demonstration of delayed eosinophil apoptosis as a mechanism causing tissue eosinophilia." Journal of Immunology 158, no. 8 (April 15, 1997): 3902–8. http://dx.doi.org/10.4049/jimmunol.158.8.3902.
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Abstract Nasal polyps, which often occur in association with allergic rhinitis and asthma, are characterized by a marked infiltration of eosinophils. Using a method for detecting eosinophils with DNA strand breaks, we found direct evidence for inhibition of eosinophil apoptosis in this model of tissue eosinophilia. By using Southern blot analysis linked to reverse transcription-PCR, we detected a mRNA signal specific for IL-5 in all nasal polyps. The identification of IL-5 as a major eosinophil survival factor was confirmed by ELISA measurements using tissue homogenates. Moreover, immunohistochemical analysis of the nasal polyp tissues demonstrated that IL-5 was localized in lymphocytes, mast cells, and eosinophils. Treatment of the eosinophil-infiltrated tissue with neutralizing anti-IL-5 mAb induced eosinophil apoptosis and decreased tissue eosinophilia. Therefore, IL-5 may represent an important cytokine responsible for the delay of the death process in eosinophils in nasal polyps. In addition, a previously suggested IL-4-dependent specific recruitment of eosinophils into the inflamed tissue could be excluded by our studies. Taken together, these findings suggest a novel mechanism by which eosinophils specifically accumulate in pathologic human tissues.
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Singh, Devender Pal, S. S. Dogra, Munish Saroch, Bal Chander, Sudesh Kumar, and Ankush Sharma. "Association between Blood Eosinophil Count and Tissue Eosinophil Grading Among Patients Suffering From Sinonasal Polyposis Attending Tertiary Care Hospital." International Academic Research Journal of Surgery 2, no. 03 (June 20, 2022): 1–5. http://dx.doi.org/10.47310/iarjs.2022.v02i03.001.
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Background: Present study aimed to evaluate the association between blood eosinophil count and tissue eosinophil grading among Patients suffering from Sinonasal Polyposis attending routine ENT OPD in Dr. RPGMC Tanda. Material and Methods: The present study was done as a hospital based cross sectional study in the department of ENT and Head and Neck Surgery, in Dr. RPGMC Kangra at Tanda. It was done in 30 patients of chronic rhinosinusitis with nasal polyposis (CRSwNP) from June 2018 to June 2019 who met the inclusion criteria. Data regarding Blood and Tissue eosinophil count was retrieved. Results: in the present study,there were a total of 30 patients out of which there were 16 males and 14 females. The mean age observed of patients was 42.47±13.68. Among the total, 17 patients were classified as Eosinophilic Chronic Rhinosinusitis with Nasal Polyposis (ECRSwNP) while 13 were classified as Non-Eosinophilic Chronic Rhinosinusitis with Nasal Polyposis (NECRSwNP). There were 9 cases of ECRSwNP where tissue eosinophils were >10/HPF while 8 cases had less than 10 tissue eosinophils/HPF. Similarly 9 cases of NECRSwNP had less than 10 tissue eosinophils/HPF while 4 cases had tissue eosinophils were >10/HPF. The association between blood eosinophil count and tissue eosinophil grading was not significant with p value of 0.225. Conclusion: Present study concluded that there was no significant association of blood eosinophil count between NECRSwNP and ECRSwNP with tissue eosinophils.
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Xu, S., M. Vallei, J. Hwang Siok Gek, C. Tze Choong, and N. Wei Yang Teo. "Endotyping of nasal polyps in a multiracial Asian population." Rhinology Online 5, no. 5 (October 14, 2022): 142–48. http://dx.doi.org/10.4193/rhinol/22.026.
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Background: Chronic rhinosinusitis is a heterogenous disease with variation in the endotypes of nasal polyps, with type 2 inflammation being more prevalent in Caucasian populations whereas Chinese populations are more heterogenous. We aim to describe the variation in endotypes for patients with chronic rhinosinusitis with nasal polyposis in our unique multiracial population. Methodology: Demographic, clinical and structured histopathological data of 66 patients who underwent sinus surgery for nasal polyposis were evaluated retrospectively. Results: 54.6% had eosinophilic disease, and 45.4% had non-eosinophilic disease with no significant demographic differences between the 2 populations. There were significantly higher peripheral eosinophil levels in patients with eosinophil-predominant inflammation on tissue histology (mean absolute eosinophil count 0.59 ± 0.18 x 109) compared with non-eosinophilic disease (mean absolute eosinophil count 0.24 ± 0.11 x 109). Structured histopathological reporting revealed that patients with eosinophilic disease had higher degree of inflammation and eosinophil aggregates. Conclusions: Our population is shown to have a slight preponderance toward eosinophilic disease, however the Chinese majority tended to have non-eosinophilic disease. Serum eosinophilia and the presence of asthma seems to correlate well with tissue eosinophilia, which can potentially be utilised as markers of type 2 inflammatory disease.
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Hancox, Robert J., Ian D. Pavord, and Malcolm R. Sears. "Associations between blood eosinophils and decline in lung function among adults with and without asthma." European Respiratory Journal 51, no. 4 (March 21, 2018): 1702536. http://dx.doi.org/10.1183/13993003.02536-2017.
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Eosinophilic inflammation and airway remodelling are characteristic features of asthma, but the association between them is unclear. We assessed associations between blood eosinophils and lung function decline in a population-based cohort of young adults.We used linear mixed models to analyse associations between blood eosinophils and spirometry at 21, 26, 32 and 38 years adjusting for sex, smoking, asthma and spirometry at age 18 years. We further analysed associations between mean eosinophil counts and changes in spirometry from ages 21 to 38 years.Higher eosinophils were associated with lower forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratios and lower FEV1 % predicted values for both pre- and post-bronchodilator spirometry (all p-values ≤0.048). Although eosinophil counts were higher in participants with asthma, the associations between eosinophils and spirometry were similar among participants without asthma or wheeze. Participants with mean eosinophil counts >0.4×109 cells·L−1 between 21 and 38 years had greater declines in FEV1/FVC ratios (difference 1.8%, 95% CI 0.7–2.9%; p=0.001) and FEV1 values (difference 3.4% pred, 95% CI 1.5–5.4% pred); p=0.001) than those with lower counts.Blood eosinophils are associated with airflow obstruction and enhanced decline in lung function, independently of asthma and smoking. Eosinophilia is a risk factor for airflow obstruction even in those without symptoms.
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Strath, M., and C. J. Sanderson. "Production and functional properties of eosinophils from bone marrow cultures." Journal of Cell Science 74, no. 1 (March 1, 1985): 207–17. http://dx.doi.org/10.1242/jcs.74.1.207.
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Bone marrow cultures have been established from mice infected with Mesocestoides corti and undergoing parasitic eosinophilia. In the absence of added conditioned medium, eosinophil differentiation ceases, and eosinophils are undetectable by 7 days, whereas neutrophil production continues over several weeks as with normal bone marrow. Eosinophil production can be induced by adding pokeweed mitogen-stimulated spleen supernatants (MSSS) or specific antigen-stimulated spleen supernatants (ASSS) produced from-spleen cells of M. corti-infected mice. In contrast to the continuous production of neutrophils, eosinophil production is transient, suggesting that there is no continued production of eosinophil progenitor cells in these cultures. More eosinophils are produced when MSSS is added at the initiation of cultures, compared to after a delay of 2 weeks, and establishing the cultures at 33 degrees C does not appear to enhance eosinophil production. The eosinophils produced are shown to express the eosinophil differentiation antigen defined by monoclonal antibody NIMP-R13, they produce eosinophil peroxidase in similar amounts to eosinophils taken from mice. They show normal phagocytic activity of antibody-coated erythrocytes and lyse red cells coated with antibodies of IgG1, IgG2a, IgG2b, but not IgM isotypes.
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Reppucci, Jennifer, Michael Chang, Steven Hughes, and Xiuli Liu. "Eosinophilic Pancreatitis: A Rare Cause of Recurrent Acute Pancreatitis." Case Reports in Gastroenterology 11, no. 1 (March 3, 2017): 120–26. http://dx.doi.org/10.1159/000457788.
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Eosinophilic pancreatitis is a rare form of recurrent acute pancreatitis that demonstrates distinct histologic features, including diffuse, periductal, acinar, and septal inflammatory infiltrates comprised of a pure or predominant population of eosinophils, eosinophilic phlebitis and arteritis, and localized eosinophilic infiltrates with pseudocyst formation. It is associated with elevated serum immunoglobulin E levels, an elevated eosinophil count with systemic manifestations, and eosinophilic infiltrates in other organs of the gastrointestinal tract. We present a case of eosinophilic pancreatitis in a 44-year-old man who was diagnosed after pancreatic resection for recurrent bouts of acute pancreatitis. While the gross and histologic evaluations matched other reported cases of eosinophilic pancreatitis, our patient had only minimal peripheral eosinophilia, no reported history of symptoms related to elevated eosinophilia or immunoglobulin E, and only mild eosinophilic infiltrates in his gallbladder.
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Driss, Virginie, Fanny Legrand, Emmanuel Hermann, Sylvie Loiseau, Yann Guerardel, Laurent Kremer, Estelle Adam, Gaëtane Woerly, David Dombrowicz, and Monique Capron. "TLR2-dependent eosinophil interactions with mycobacteria: role of α-defensins." Blood 113, no. 14 (April 2, 2009): 3235–44. http://dx.doi.org/10.1182/blood-2008-07-166595.
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AbstractPeripheral blood and tissue eosinophilia are a prominent feature in allergic diseases and during helminth infections. Eosinophil recruitment also frequently occurs upon mycobacterial infections, particularly in lung granuloma. However, the mechanism by which eosinophils interact with mycobacteria remains largely unknown. Because eosinophils recently have been shown to be involved in innate immune responses, we investigated the direct interactions of eosinophils with Mycobacterium bovis BCG as a study model. We show that live BCG attracts human eosinophils and induces reactive oxygen species (ROS) synthesis, granule protein release, and tumor necrosis factor (TNF)–α secretion. Using anti-TLR2 neutralizing antibodies before exposure of eosinophils to BCG, we showed a critical role of TLR2 signaling in ROS and eosinophil peroxidase release. BCG-induced eosinophil activation is mediated through the p38 mitogen-activated protein (MAP) kinase and nuclear factor (NF)–κB pathways. In addition, a mycobacterial wall component, lipomannan, induced a TLR2-dependent eosinophil activation. In addition, we showed that eosinophils express and produce α-defensins upon stimulation with BCG and lipomannan and that α-defensins could inhibit mycobacterial growth in synergy with eosinophil cationic protein. These results suggest a role for human eosinophils as direct effectors in TLR2-mediated innate immunity against mycobacteria and confer to these cells potent cytotoxic functions through defensin and eosinophil cationic protein production.
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Brussino, L., E. Heffler, C. Bucca, S. Nicola, and G. Rolla. "Eosinophils Target Therapy for Severe Asthma: Critical Points." BioMed Research International 2018 (October 25, 2018): 1–6. http://dx.doi.org/10.1155/2018/7582057.
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Asthma is a chronic and heterogeneous disease, which is defined as severe disease whenever it requires treatment with a high dose of inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming ‘‘uncontrolled’’ or if it remains ‘‘uncontrolled’’ despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma, which is characterized by sputum eosinophilia, associated with mild to moderate increase in blood eosinophil count, frequently adult-onset, and associated with chronic rhinosinusitis with nasal polyps in half of the cases. Eosinophilic asthma is driven by T2 inflammation, characterized, among the others, by interleukin-5 production. IL-5 plays a key role in the differentiation, survival, migration, and activation of eosinophils, and it has become an appealing therapeutic target for eosinophilic asthma. In recent years two monoclonal antibodies (mepolizumab and reslizumab) directed against IL-5 and one monoclonal antibody directed against the alpha-subunit of the IL-5 receptor (benralizumab) have been developed. All these IL-5 target drugs have been shown to reduce the number of exacerbation in patients with severe asthma selected on the basis of peripheral blood eosinophil count. There are still a number of unresolved issues related to the anti-IL5 strategy in eosinophilic asthma, which are here reviewed. These issues include the effects of such therapy on airway obstruction and asthmatic symptoms, the level of baseline eosinophils that predicts a response to treatment, the relationship between blood and airway eosinophilia, and, perhaps most importantly, how to elucidate the pathogenetic role played by eosinophils in the individual patient with severe eosinophilic asthma.
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Weng, M., D. M. Baron, K. D. Bloch, A. D. Luster, J. J. Lee, and B. D. Medoff. "Eosinophils are necessary for pulmonary arterial remodeling in a mouse model of eosinophilic inflammation-induced pulmonary hypertension." American Journal of Physiology-Lung Cellular and Molecular Physiology 301, no. 6 (December 2011): L927—L936. http://dx.doi.org/10.1152/ajplung.00049.2011.
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There is increasing evidence that inflammation plays a pivotal role in the pathogenesis of some forms of pulmonary hypertension (PH). We recently demonstrated that deficiency of adiponectin (APN) in a mouse model of PH induced by eosinophilic inflammation increases pulmonary arterial remodeling, pulmonary pressures, and the accumulation of eosinophils in the lung. Based on these data, we hypothesized that APN deficiency exacerbates PH indirectly by increasing eosinophil recruitment. Herein, we examined the role of eosinophils in the development of inflammation-induced PH. Elimination of eosinophils in APN-deficient mice by treatment with anti-interleukin-5 antibody attenuated pulmonary arterial muscularization and PH. In addition, we observed that transgenic mice that are devoid of eosinophils also do not develop pulmonary arterial muscularization in eosinophilic inflammation-induced PH. To investigate the mechanism by which APN deficiency increased eosinophil accumulation in response to an allergic inflammatory stimulus, we measured expression levels of the eosinophil-specific chemokines in alveolar macrophages isolated from the lungs of mice with eosinophilic inflammation-induced PH. In these experiments, the levels of CCL11 and CCL24 were higher in macrophages isolated from APN-deficient mice than in macrophages from wild-type mice. Finally, we demonstrate that the extracts of eosinophil granules promoted the proliferation of pulmonary arterial smooth muscle cells in vitro. These data suggest that APN deficiency may exacerbate PH, in part, by increasing eosinophil recruitment into the lung and that eosinophils could play an important role in the pathogenesis of inflammation-induced PH. These results may have implications for the pathogenesis and treatment of PH caused by vascular inflammation.
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Fulkerson, Patricia, Kaila Schollaert, and Marc Rothenberg. "Negative regulation of eosinophil production by TLR4 ligand (153.26)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 153.26. http://dx.doi.org/10.4049/jimmunol.186.supp.153.26.
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Abstract It has long been appreciated that a drop in eosinophils is associated with acute bacterial infection while, in contrast, blood levels of monocytes and neutrophils rise. The initial eosinopenic response is believed to be secondary to margination of circulating eosinophils to blood vessel walls, but the mechanism for prolonged eosinophil depletion with bacterial infection remains undefined. In a culture system developed to differentiate mature eosinophils from low density bone marrow progenitors, IL-5 stimulation of progenitors resulted in induced expression of six TLRs with highest expression of TLR2 and TLR4 noted throughout eosinophil development. Surface expression of TLR4 was confirmed on CD34+ progenitors by FACS. Stimulation of progenitors with LPS markedly inhibited IL-5-mediated eosinophil production. Further, LPS administration in vivo specifically reduced numbers of eosinophil progenitors in the bone marrow. Treatment of developing eosinophils with LPS induced the generation of pro-inflammatory mediators, including IL-6, IL-10, IFN-γ and TNF-α, but mechanistic studies demonstrated that suppression of eosinophil production by LPS was independent of these mediators. Taken together, these findings suggest a direct effect of LPS on eosinophil progenitors as an explanation for eosinopenia following bacterial infections and a potentially novel therapeutic strategy for depleting eosinophil progenitors and inhibiting peripheral eosinophilia in eosinophil-associated diseases.
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Fedorov, I. A., and O. G. Rybakova. "Laboratory Dynamics in Children With Mild Persistent Bronchial Asthma." Doctor.Ru 19, no. 10 (2020): 48–51. http://dx.doi.org/10.31550/1727-2378-2020-19-10-48-51.
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Study Objective: to track the laboratory dynamics in children with mild persistent bronchial asthma (BA) at various stages of disease with or without baseline therapy. Study Design: prospective cohort study. Materials and Methods. The study included 42 patients with mild persistent BA aged 5 to 16 years. Each child was followed up for 3 years. At initiation of the study and during each visit, all patients had their blood eosinophils, nasal discharge (ND) and induced sputum (IS), as well as serum eosinophil cation protein (ECP) tested; and their respiratory function was assessed. All children were prescribed baseline therapy with low doses of inhalative glucocorticosteroids (GCS); 18 children also received allergen-specific immunotherapy (ASIT). Study Results. Inhalative GCS for BA exacerbations facilitated normalisation of sputum, ND and blood eosinophils. During periods of BA remission, ND and IS eosinophil levels increased, but patients did not have rhinitis and BA symptoms. Eosinophil levels in IS were higher vs. BA control (р = 0.05) and lower vs. disease exacerbations (р < 0.05). We did not find any differences in laboratory results in children with or without ASIT who were treated with low doses of inhalative and nasal GCS. Conclusion. Eosinophile inflammatory phenotype in patients did not charge depending on disease duration and control therapies. According to the study data, eosinophile levels in IS, when BA exacerbation was recorded, were 8.0% [3.0–16.0%]. This value can be used as an additional predictor for the need in increased therapy (a step forward). Irrespective of the disease stage and therapy, there was correlation between blood eosinophile level and IS eosinophile level and between IS eosinophile level and blood ECP concentration. Keywords: bronchial asthma, children, eosinophiles, induced sputum, inflammatory phenotype.
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Baptista-dos-Reis, Renata, Valdirene S. Muniz, and Josiane S. Neves. "Multifaceted Roles of Cysteinyl Leukotrienes in Eliciting Eosinophil Granule Protein Secretion." BioMed Research International 2015 (2015): 1–7. http://dx.doi.org/10.1155/2015/848762.
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Cysteinyl leukotrienes (cysLTs) are cell membrane-impermeant lipid mediators that play major roles in the pathogenesis of eosinophilic inflammation and are recognized to act via at least 2 receptors, namely, cysLT1receptor (cysLT1R) and cysLT2receptor (cysLT2R). Eosinophils, which are granulocytes classically associated with host defense against parasitic helminthes and allergic conditions, are distinguished from leukocytes by their dominant population of cytoplasmic crystalloid (also termed secretory, specific, or secondary) granules that contain robust stores of diverse preformed proteins. Human eosinophils are the main source of cysLTs and are recognized to express both cysLTs receptors (cysLTRs) on their surface, at the plasma membrane. More recently, we identified the expression of cysLTRs in eosinophil granule membranes and demonstrated that cysLTs, acting via their granule membrane-expressed receptors, elicit secretion from cell-free human eosinophil granules. Herein, we review the multifaceted roles of cysLTs in eliciting eosinophil granule protein secretion. We discuss the intracrine and autocrine/paracrine secretory responses evoked by cysLTs in eosinophils and in cell-free extracellular eosinophil crystalloid granules. We also discuss the importance of this finding in eosinophil immunobiology and speculate on its potential role(s) in eosinophilic diseases.
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Schollaert, Kaila L., Melissa K. Mingler, Marc E. Rothenberg, and Patricia C. Fulkerson. "Negative Regulation of Eosinophil Production by Toll-Like Receptors." Blood 120, no. 21 (November 16, 2012): 1237. http://dx.doi.org/10.1182/blood.v120.21.1237.1237.
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Abstract Abstract 1237 Eosinophilia is a common clinical problem associated with numerous disorders such as atopic diseases, parasitic infections, hypereosinophilic syndrome (HES), and cancer. A marked decrease in circulating eosinophils, or eosinopenia, has long been associated with acute bacterial infections. Eosinopenia has been shown to be a sensitive and reliable marker for distinguishing between non-infectious and infection-associated sepsis in the intensive care unit setting. Eosinopenia with acute infection had been assumed to be secondary to the release of adrenal glucocorticoids in response to the stress of infection. However, animal studies performed in the 1970s demonstrated that inhibition of parasite-associated eosinophilia with acute bacterial infection was independent of adrenal stimulation; the investigator speculated that it was due to a direct effect on the eosinophil precursor. To date, the mechanism of infection-associated eosinopenia, and its potential for suppressing IL-5-mediated eosinophilia, has not been investigated. To study eosinophil development, we established an ex vivo liquid culture system in which we can follow the differentiation of murine eosinophil lineage-committed progenitors (EoPs) to mature functional effector eosinophils that express known eosinophil surface markers and granule proteins and respond to eosinophil-active chemoattractants. We demonstrate that murine eosinophil precursors express mRNA for six TLRs. Ligands for TLR2 heterodimers, TLR4 and TLR7, but not TLR3, inhibited eosinophil ex vivo growth by attenuating EoP proliferation in response to IL-5 stimulation. Exposure to heat-killed E. coli also resulted in diminished EoP proliferation. The developing eosinophils further responded to TLR activation with production of a subset of inflammatory cytokines, including IL-6, IL-10, TNF-alpha and CXCL10. Co-culturing of untreated EoPs with LPS-exposed EoPs resulted in reduced IL-5-mediated proliferation of the untreated EoPs, suggesting that EoPs secrete mediators in response to TLR activation that regulate their proliferation in an autocrine/paracrine manner. Neutralization of IFN-beta, but not IFN-alpha or IFN-gamma, partially protected developing eosinophils from the inhibitory effects of LPS. In vivo studies revealed that endotoxemia and bacteremia reduced numbers of EoPs in the bone marrow of wild-type mice. Further, LPS dose-dependently reduced hypereosinophilia in IL-5 transgenic mice, highlighting the potential therapeutic value of this approach even in an extreme IL-5-driven clinical state. Suppression of eosinophil production by TLR4 ligands is conserved between mice and humans as yield of eosinophils from human EoPs was reduced following LPS exposure. Taken together, these findings identify a mechanistic explanation for eosinopenia following bacterial infections and identify a novel therapeutic strategy for inhibiting eosinophil production and peripheral eosinophilia in eosinophil-associated diseases. Disclosures: No relevant conflicts of interest to declare.
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Diny, Nicola, Xuezhou Hou, Jobert G. Barin, Monica V. Talor, Noel R. Rose, and Daniela Cihakova. "The eotaxin-CCR3 pathway is required for eosinophil trafficking to the heart in eosinophilic myocarditis." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 117.10. http://dx.doi.org/10.4049/jimmunol.196.supp.117.10.
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Abstract Cardiac manifestations are a major cause of morbidity and mortality in patients with eosinophil-associated diseases. Eosinophils have been proposed to play a pathologic role in the heart. Nevertheless, the pathways that recruit eosinophils to the heart have not been described. In IFNγ−/− IL-17A−/− mice, induction of experimental autoimmune myocarditis results in a Th-2-driven, eosinophilic inflammation. IFNγ−/− IL-17A−/− mice had much higher expression of the eosinophil-attracting chemokines eotaxin-1 (Ccl11) and eotaxin-2 (Ccl24) in the heart than wildtype mice. Genetic ablation of the eotaxin receptor CCR3 resulted in a dramatic decrease in heart infiltrating eosinophils. Adoptive transfer experiments with CCR3+/+ or CCR3−/− eosinophils into eosinophil-deficient ΔdblGATA1 or IFNγ−/− IL-17A−/− ΔdblGATA1 recipients showed that two conditions have to be met for efficient eosinophil trafficking to the inflamed heart: high eotaxin expression in the heart and expression of CCR3 by eosinophils. We identified the source of cardiac eotaxins by RT-PCR of FACS sorted heart cells and by immunohistochemistry. Eotaxin-1 was mainly produced by cardiac fibroblasts with interstitial localization in the heart. In vitro culture of cardiac fibroblasts with IL-4 and IL-13 induced eotaxin-1 expression. In contrast, eotaxin-2 was expressed by multiple inflammatory cell types, located at inflammatory foci, and substantial expression was only found in mice lacking IFNγ and IL-17A during myocarditis. In conclusion, eosinophil trafficking to the heart is dependent on the eotaxin-CCR3 pathway in mice with eosinophilic myocarditis. Blockade of this pathway may be a useful therapeutic approach to prevent eosinophil-mediated heart damage.
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Chu, Hanh Hong, Yoshiki Kobayashi, Dan Van Bui, Yasutaka Yun, Linh Manh Nguyen, Akitoshi Mitani, Kensuke Suzuki, Mikiya Asako, Akira Kanda, and Hiroshi Iwai. "CCL4 Regulates Eosinophil Activation in Eosinophilic Airway Inflammation." International Journal of Molecular Sciences 23, no. 24 (December 18, 2022): 16149. http://dx.doi.org/10.3390/ijms232416149.
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Eosinophilic chronic rhinosinusitis (ECRS) is a refractory airway disease accompanied by eosinophilic inflammation, the mechanisms of which are unknown. We recently found that CCL4/MIP-1β—a specific ligand for CCR5 receptors—was implicated in eosinophil recruitment into the inflammatory site and was substantially released from activated eosinophils. Moreover, it was found in nasal polyps from patients with ECRS, primarily in epithelial cells. In the present study, the role of epithelial cell-derived CCL4 in eosinophil activation was investigated. First, CCL4 expression in nasal polyps from patients with ECRS as well as its role of CCL4 in eosinophilic airway inflammation were investigated in an in vivo model. Furthermore, the role of CCL4 in CD69 expression—a marker of activated eosinophils—as well as the signaling pathways involved in CCL4-mediated eosinophil activation were investigated. Notably, CCL4 expression, but not CCL5, CCL11, or CCL26, was found to be significantly increased in nasal polyps from patients with ECRS associated with eosinophil infiltration as well as in BEAS-2B cells co-incubated with eosinophils. In an OVA-induced allergic mouse model, CCL4 increased eosinophil accumulation in the nasal mucosa and the bronchoalveolar lavage (BALF). Moreover, we found that CD69 expression was upregulated in CCL4-stimulated eosinophils; similarly, phosphorylation of several kinases, including platelet-derived growth factor receptor (PDGFR)β, SRC kinase family (Lck, Src, and Yes), and extracellular signal-regulated kinase (ERK), was upregulated. Further, CCR5, PDGFRβ, and/or Src kinase inhibition partially restored CCL4-induced CD69 upregulation. Thus, CCL4, which is derived from airway epithelial cells, plays a role in the accumulation and activation of eosinophils at inflammatory sites. These findings may provide a novel therapeutic target for eosinophilic airway inflammation, such as ECRS.
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Moreira, Alvaro, Michael Erdmann, Ugur Uslu, Verona Vass, Gerold Schuler, and Beatrice Schuler-Thurner. "Blood Eosinophilia Is an on-Treatment Biomarker in Patients with Solid Tumors Undergoing Dendritic Cell Vaccination with Autologous Tumor-RNA." Pharmaceutics 12, no. 3 (March 1, 2020): 210. http://dx.doi.org/10.3390/pharmaceutics12030210.
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Background: The approvals of immune checkpoint inhibitors for several cancer types and the rapidly growing recognition that T cell-based immunotherapy significantly improves outcomes for cancer patients led to a re-emergence of cancer vaccines, including dendritic cell (DC)-based immunotherapy. Blood and tissue biomarkers to identify responders and long-term survivors and to optimize cost and cost-effectiveness of treatment are greatly needed. We wanted to investigate whether blood eosinophilia is a predictive biomarker for patients with solid tumors receiving vaccinations with DCs loaded with autologous tumor-RNA. Methods: In total, 67 patients with metastatic solid tumors, who we treated with autologous monocyte-derived DCs transfected with total tumor mRNA, were serially analyzed for eosinophil counts and survival over the course of up to 14 years. Eosinophilic counts were performed on peripheral blood smears. Results: Up to 87% of the patients treated with DC-based immunotherapy experienced at least once an eosinophilia of ≥ 5% after initiation of therapy; 61 % reached levels of ≥ 10% eosinophils, and 13% of patients showed eosinophil counts of 20% or above. While prevaccination eosinophil levels were not associated with survival, patients with blood eosinophilia at any point after initiation of DC-based immunotherapy showed a trend towards longer survival. There was a statistically significant difference for the patients with eosinophil counts of 20% or more (p = 0.03). In those patients, survival was prolonged to a median of 58 months (range 2–111 months), compared to a median of 20 months (range 0–119 months) in patients with lower eosinophil counts. In 12% of the patients, an immediate increase in eosinophil count of at least 10 percentage points could be detected after the first vaccine, which also appeared to correlate with survival (65 vs. 24 months; p = 0.06). Conclusion: Blood eosinophilia appears to be an early, on-therapy biomarker in patients with solid tumors undergoing vaccination with RNA-transfected DC, specifically autologous tumor mRNA-transfected DC vaccines, and it correlates with long-term patient outcome. Eosinophilia should be systematically investigated in future trials.
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Kolobovnikova, Yu V., O. I. Urazova, and V. V. Novitskiy. "PECULIARITIES OF THE FUNCTIONAL ACTIVITY OF BLOOD EOSINOPHIL GRANULOCYTES IN PULMONARY TUBERCULOSIS." Bulletin of Siberian Medicine 13, no. 5 (October 28, 2014): 42–48. http://dx.doi.org/10.20538/1682-0363-2014-5-42-48.
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Eosinophils are polyfunctional leukocytes detected in excess in blood and in the focus of granulomatous inflammation in pulmonary TB.The research objective was to evaluate the adhesive properties as well as cytokine-secretory and antibacterial activity of blood eosinophils in pulmonary TB.The research has been conducted on eosinophils isolated from peripheral blood of 43 patients with freshly identified progressive destructive TB with and without eosinophilia. Using flow cytometry and ELISA, expression of CD9 and CD18 adhesion molecules on blood eosinophils has been studied along with the phagocyte and cytokine-secretory functions and activity of eosinophil granulocyte peroxidase.As a result of the research it has been established that in TB patients with eosinophilia the number of CD18-expressing eosinophils rises, whereas the amount of CD9+ remains within norm. Activation of the phagocyte function of blood eosinophil granulocytes is associated with the decrease in eosinophil peroxidase activity, while the increase in IL-5 and TNFα secretory reactivity is connected with oppositely directed changes in IL-2 basal secretion by eosinophils in vitro (a fall in infiltrative TB and a rise in disseminated TB).
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Broide, David H., Keith Campbell, Tim Gifford, and P. Sriramarao. "Inhibition of eosinophilic inflammation in allergen-challenged, IL-1 receptor type 1–deficient mice is associated with reduced eosinophil rolling and adhesion on vascular endothelium." Blood 95, no. 1 (January 1, 2000): 263–69. http://dx.doi.org/10.1182/blood.v95.1.263.
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Abstract To determine the relative in vivo importance of IL-1 release after allergen challenge to the subsequent endothelial adhesion and recruitment of eosinophils, the authors used ovalbumin sensitization and inhalation challenge to induce airway eosinophilia in IL-1 receptor type 1-deficient and control wild-type mice. Bronchoalveolar lavage (BAL) eosinophil recruitment in IL-1 receptor type 1-deficient mice challenged with ovalbumin (24.3% ± 6.3% BAL eosinophils) was significantly reduced compared with wild-type mice (63.7% ± 2.5% BAL eosinophils). To determine whether the inhibition of eosinophil adhesion to vascular endothelium contributed to the inhibition of eosinophil recruitment in IL-1 receptor type 1-deficient mice, the authors used intravital microscopy to visualize the rolling and firm adhesion of fluorescence-labeled mouse eosinophils in the microvasculature of the allergen-challenged mouse mesentery. Eosinophil rolling, eosinophil firm adhesion to endothelium, and transmigration across endothelium (peritoneal eosinophils) were significantly inhibited in allergen-challenged IL-1 receptor type 1-deficient mice compared with wild-type mice. Overall, these studies demonstrate that cytokines such as IL-1, released after allergen challenge, are important in the induction of endothelial cell adhesiveness, a prerequisite for the recruitment of circulating eosinophils. (Blood. 2000;95:263-269)
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Broide, David H., Keith Campbell, Tim Gifford, and P. Sriramarao. "Inhibition of eosinophilic inflammation in allergen-challenged, IL-1 receptor type 1–deficient mice is associated with reduced eosinophil rolling and adhesion on vascular endothelium." Blood 95, no. 1 (January 1, 2000): 263–69. http://dx.doi.org/10.1182/blood.v95.1.263.001k02_263_269.
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To determine the relative in vivo importance of IL-1 release after allergen challenge to the subsequent endothelial adhesion and recruitment of eosinophils, the authors used ovalbumin sensitization and inhalation challenge to induce airway eosinophilia in IL-1 receptor type 1-deficient and control wild-type mice. Bronchoalveolar lavage (BAL) eosinophil recruitment in IL-1 receptor type 1-deficient mice challenged with ovalbumin (24.3% ± 6.3% BAL eosinophils) was significantly reduced compared with wild-type mice (63.7% ± 2.5% BAL eosinophils). To determine whether the inhibition of eosinophil adhesion to vascular endothelium contributed to the inhibition of eosinophil recruitment in IL-1 receptor type 1-deficient mice, the authors used intravital microscopy to visualize the rolling and firm adhesion of fluorescence-labeled mouse eosinophils in the microvasculature of the allergen-challenged mouse mesentery. Eosinophil rolling, eosinophil firm adhesion to endothelium, and transmigration across endothelium (peritoneal eosinophils) were significantly inhibited in allergen-challenged IL-1 receptor type 1-deficient mice compared with wild-type mice. Overall, these studies demonstrate that cytokines such as IL-1, released after allergen challenge, are important in the induction of endothelial cell adhesiveness, a prerequisite for the recruitment of circulating eosinophils. (Blood. 2000;95:263-269)
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Linch, Stefanie N., Ann M. Kelly, Erin T. Danielson, Ralph Pero, James J. Lee, and Jeffrey A. Gold. "Mouse Eosinophils Possess Potent Antibacterial Properties In Vivo." Infection and Immunity 77, no. 11 (August 24, 2009): 4976–82. http://dx.doi.org/10.1128/iai.00306-09.
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ABSTRACT Eosinophils are best known as the predominant cellular infiltrate associated with asthma and parasitic infections. Recently, numerous studies have documented the presence of Toll-like receptors (TLRs) on the surfaces of eosinophils, suggesting that these leukocytes may participate in the recognition and killing of viruses and bacteria. However, the significance of this role in the innate immune response to bacterial infection is largely unknown. Here we report a novel role for eosinophils as antibacterial defenders in the host response. Isolated mouse eosinophils possessed antipseudomonal properties in vitro. In vivo, interleukin-5 transgenic mice, which have profound eosinophilia, demonstrated improved clearance of Pseudomonas aeruginosa introduced into the peritoneal cavity. The findings of improved bacterial clearance following adoptive transfer of eosinophils, and impaired bacterial clearance in mice with a congenital eosinophil deficiency, established that this effect was eosinophil specific. The data presented also demonstrate that eosinophils mediate this antibacterial effect in part through the release of cationic secondary granule proteins. Specifically, isolated eosinophil granules had antibacterial properties in vitro, and administration of eosinophil granule extracts significantly improved bacterial clearance in vivo. These data suggest a potent yet underappreciated antibacterial role for eosinophils in vivo, specifically for eosinophil granules. Moreover, the data suggest that the administration of eosinophil-derived products may represent a viable adjuvant therapy for septic or bacteremic patients in the intensive care unit.
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Casanova, Ciro, Bartolome R. Celli, Juan P. de-Torres, Cristina Martínez-Gonzalez, Borja G. Cosio, Victor Pinto-Plata, Pilar de Lucas-Ramos, et al. "Prevalence of persistent blood eosinophilia: relation to outcomes in patients with COPD." European Respiratory Journal 50, no. 5 (November 2017): 1701162. http://dx.doi.org/10.1183/13993003.01162-2017.
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The impact of blood eosinophilia in chronic obstructive pulmonary disease (COPD) remains controversial.To evaluate the prevalence and stability of a high level of blood eosinophils (≥300 cells·μL–1) and its relationship to outcomes, we determined blood eosinophils at baseline and over 2 years in 424 COPD patients (forced expiratory volume in 1 s (FEV1) 60% predicted) and 67 smokers without COPD from the CHAIN cohort, and in 308 COPD patients (FEV1 60% predicted) in the BODE cohort. We related eosinophil levels to exacerbations and survival using Cox hazard analysis.In COPD patients, 15.8% in the CHAIN cohort and 12.3% in the BODE cohort had persistently elevated blood eosinophils at all three visits. A significant proportion (43.8%) of patients had counts that oscillated above and below the cut-off points, while the rest had persistent eosinophil levels <300 cells·μL–1. A similar eosinophil blood pattern was observed in controls. Exacerbation rates did not differ in patients with and without eosinophilia. All-cause mortality was lower in patients with high eosinophils compared with those with values <300 cells·μL–1 (15.8% versus 33.7%; p=0.026).In patients with COPD, blood eosinophils ≥300 cells·μL–1 persisting over 2 years was not a risk factor for COPD exacerbations. High eosinophil count was associated with better survival.